Process for synthesizing vitamin b6



- amino-B-methyl pyridine which, when subjectedcyano-4-carboxy-fi-methyl Pyfldwe-Mnremred Patented Feb. 2, 1943 I IUNITED STATES PATENT OFFICE PROCESS FOR SWTEESIZING VITAMIN Be Gustaf H.Carlson, Pearl River, N. Y., assignor to Lederle Laboratories, Inc., NewYork, N. Y., a corporation of Delaware No Drawing. Application September26, 1941;

Serial No. 412,427

18 Claims. (CL 260-297) This invention relates to synthetic methods ofaralkyl, or heterocyclic and X represents bromine preparing vitamins andmore particularly reor chlorine. lates to an improved process for thepreparation It is an advantage oi the present invention 01 vitamin Baandto new intermediates employed that the reagen s a s p v h n th in theprocess. A 5 reagents employed in the long and involved In accordancewith the present invention, I process described in the-"literature forthe prepahave discovered that vitamin B5 may be syntheration or vitaminBe. It is also an advantage of sized by a series of steps whichcomprises rethis invention that a process is provided which acting anester of 3-cyano-4-carboxy-G-methyl r. ives a od ver-all yie d of Viamin B6- pyridone-2 with ammonia to form the amide of 1 My improvedprocess for prod n Vit in 6 3-cyano-4-carboxy-6-methyl pyridone-2 whichis will be more fully illustrated in conjunction with dehydrated to3,4-dicyano-6-methyl pyridone-2, the following specific examples. Itshould be and this product nitrated to form the compound understood,however, that the examples are given 3,4-dicyano-5-nitro-6-methylpyridone-Z, which, merely by way of illustration and the invention byhaiogenation, is converted to 2-halo-3A-di- 1 is not to be limited bythe exact details set forth cyano-5-nitro 6 methyl pyridin. This lattertherein. compound is partially reduced to give 2-halo-3,4-dicyano-5-amino-6-methyl pyridin and this am- Prep-Mam Zi$i$ffl 4 incderivative is then subjected to a more comm t reduction step t form3,4-am1nomethy1-5- Two hundred grams of the ethyl ester of 3- to adeamination treatment (replacement of 'acmrdmg the method described byBardhan NH2 by OH)' gives vitamin B6 3 4 h J. C. S. 2223 (1929)) wereadded 130 3.5 liters of methyl-5-oxy-6-meth 1 pyridin), absolutemethanol saturated at 0 C. with gase- The reactions which take place inthe above one ammonia. and, after '7 days at 0 0., the steps may berepresented as fouows:- filtered solution was concentrated in vacuo to asmall volume to give the amide oi 3-cyano-4- carboxy-6-methylpyridone-2, which melted above 300 C. with decomposition. The compoundso prepared is'useful as an intermediate 2%., W in the synthesis orvitamin B8.

h CH Nf gi gf gi In the foregoing specific example the ethyl COOR CONH:

Q ing agent 4 ester of 3-cyano-4-carboxy-6-methy1 pyndone-Z H wasemployed in CN is the preferred v and availability. It should beunderstood, how- CN' BNO; N0 0N P01, ever, that the ethyl ester may bereplaced by 55; other suitable esters of 3-cyano-4-carboxy-6- c 2 oH,-=o methyl pyridone-2. Among tne various esters I I 40 that may beemployed are the alkyl esters such thyl, may similarly be employed.Esters of the o 0N H NH 0N H aralkyl type which may be satisfactory arethose N I I v such as the benzyl ester and the ester of 2-hy- X CH x Pddroxymethylnaphthalene, cinnamyl alcohol, etc.

N r \N/ The esters derived from cycloaliphatic alcohols fl GENE, CECEsuch as cyciohexanol, methyl cyclohexanol,

. heterocyclic alcohols, for'example furfuryl alco- 015K CH hol,tetrahydrofurfuryl alcohol or those derived x N N from nitro alcoholssuch as 2-nitro-2-Inethyl-1- propanol are not precluded from the presentinin which R represents radicals such as alkyl, aryl, vention.

01mmI BN0. T 013,013 50 of various other esters-such as those derivedfrom 'Preparation of 3,4-dicyano-6-methyl pyridone-Z not was filteredoff and recrystallized from aqueous alcohol. The pure dinitriie (0.4 g.)melted at 241-243" C. (uncorrected).

In subsequent experiments it was found to be advantageous" to employ aninert diluent in the reaction mixture and typical of such adehydrationare the following details. A mechanically stirred mixture of 50 g. ofthe amide, 250 cc. of dry toluene and 250 cc. of phosphorous oxychloridewas heated in a bath at 130-133 C. for 9.5 hours and, after hours atroom temperature, the undissolved material was filtered oil? andthoroughly extracted with toluene and ether. The solid was thenextracted with acetone and yielded 8.9 g. of unchanged amide. Theoriginal toluene filtrate and the combined toluene and ether extractswere evaporated in vacuo and the residual product was treated with cc.of ice water. The crude yellow mixture was diluted with 800 cc. of hotacetone, the insoluble product was filtered ofi, twice extracted with300 cc. of hot acetone, and yielded 11.3 g. of recovered amide. Theaqueous acetone filtrate and the combined acetone extracts wereconcentrated in vacuo to a small volume and yielded 13.4 g. of the crudedinitrile (M. P. 239-243 C.) which melted at 241-242 C. afterrecrystallization (melting points uncorrected).

Phosphorous oxychloride is the preferred dehydrating reagent in carryingout the above reaction. It should be understood, however, that any othersuitable dehydrating agent may be employed. Similarly, various otherinert solvents may be used to replace toluene.

Preparation of 3,4-dicyano-S-nitro-fi-methyl pyrz'done-Z A suspension of3,4-dicyano-6-methyl pyridone-2 (3.8 g.) in 20 cc. of acetic anhydridewas treated at 45-52 C. with a solution prepared from 3 cc. of fumingnitric acid, 3 cc. of acetic anhydride and a few crystals of urea. Theresulting solution was poured onto cracked ice and yielded 2.6 g. of thecrude nitro compound. The solid was dissolved in 75 cc. of acetone, thesolution was treated with active charcoal and the filtered solution wasconcentrated in vacuo to a small volume. The solution was rapidlydiluted with ether and the precipitated product was recrystallized iroman acetone-ether solution. The pure nitro derivative (1.6 a.) which wasobtained had a melting point of 242-244 C. uncorrected.

Preparation of 2-chZoro-3,4-dicyano-5-nitrofi-methyl pyridin Theextractwas treated with actitrated in vacuo to a small volume and, on additionof petroleum ether, yielded 5.4 g. of the crude chloro compound. Afterrecrystallization, 4.3 g. of the pure product was obtained which meltedat 86-86.5 C. uncorrected.

I prefer to use phosphorous pentachloride for halogenating the pyridone,but it should be understood, that other suitable halogenating reagentsmay be used instead, for example phosphorous pentabromlde. Similarly,the 2-chloro compound is the preferred intermediate for use Preparationof 2-chloro-3,4-dicyano-5-aminofi-methyl pyridin A solution of l g. of2-chloro-3A-dicyanc-5- nitro-fi-methyl pyridin in cc. of aceticanhydride was reduced catalytically in the usual manner (0.1 g. ofplatinum oxide used as cata lyst) and absorbed 390 cc. of hydrogenduring 160 minutes. The catalyst was filtered ofl, solvent was distilledin vacuo, the residue was washed with acetone and recrystallized fromaqueous acetone. The resulting, slightly impure amine was recrystallizedfrom acetic acid containing hydrogen chloride and then melted at221-222" C.

The reduction may be carried out using other suitable hydrogenatingcatalysts instead of platinum oxide. The reduction is preferably carriedout catalytically. It should be understood, however, that other knownreduction methods may be employed. Suitable reduction methods includereduction with metals and acid as well as the usual alkaline reductionswell known and used in the art for reduction of nitro groups.

The 2 4 chloro 3,4 dicyano-fi-nitro-fi-methyl pyridin used as thestarting material in the above reduction may be replaced by thecorresponding 2-bromo compound to result in the production of2-bromo-3,4-dicyano-5-amino-6-methyl pyridin.

Preparation of 3,4-aminomethyl-5amino- 6=methyl pyridintrihydrochlorz'de A solution of 2-chloro-3,4-dicyano-5-amino-6- methylpyridin (0.75 g.) and 0.75 g. of hydrogen chloride in 112.5 cc. ofmethanol containing 10% of water was added gradually, during 16.5 hours,to a mechanically agitated suspension of 3 g. of palladium chloride in75 cc. of 90% methanol previously reduced in the usual manner withhydrogen), and absorbed 550 cc. of hydrogen at 30 C. Sufficient waterwas added to dissolve the precipitated product, the solution wasfiltered and the filtrate was diluted with an equal volume of ether. Thecrystalline salt was washed with absolute methanol and yielded thetrihydrochloride.

The trihydrobromide may be obtained by using hydrogen bromide to replacehydrogen chloride in the above example.

The free base, 3,4-aminomet-hyl-6-methy1 pyridin, may be liberated fromthe hydrogen halides in the usual manner.

Preparation of 3,4-hudrorymethyl-5-oxy- G-methyl pyridin (B5) A solutionof 0.3 g. of 3,4-aminomethyl-5: amino-6-methyl pyridin trihydrochloridein 5 cc. of water was added simultaneously with a solution of 0.68 g. ofsodium nitrite in 5 cc. of water volume and the solution was dilutedwith acetone.

During 15 hours at C. the solution deposited a white crystallinecompound, M.'P. 201-202" C.-

uncorrected, which did not depress the melting point of an authenticspecimen of vitamin B0 (pyridoxin) and conformed in all essentials withthe properties of the known compound.

The term "deamination" as used in the specification and claims refers tothe replacement or a NH: group by 9. OH group. 7

In the deamination step described above the trihydrobromide may be used,the hydrochloride being preferred because of cheapness and ease oipreparation. Similarly, the sodium nitrite may be replaced by othersuitable ni'trites such as for example potassium nitrite and thereaction may also be eflected by using amyl nitrite in the usual way.

I claim:

1. In the process of preparing vitamin Be, the

step which comprises reduction of 2-chloro-3,4- dicyano-E-amino-G-methylpyridin to form 3,4-

' aminomethyl-E-amino-G-methyl pyridin.

10. In the process of preparing vitamin Be. the step which comprisesdeamination oi 3,4-aminomethyl-Ea-amino-ii-methyl pyridin trihydrohaLides of the group consisting of the trihydrochloride and thetrihydrobromide to form vitamin Ba.

11. In the process 01' preparing vitamin Be, the step which comprisesdeamination of 3,4-amino- .methyi-B-amino-B-methyl pyridintrihydrochloride to form vitamin Be.

12. In the process or preparing vitamin Be, the

steps which comprise reacting an ester oi. 3-

step which comprises reacting an ester of 3- cyano-i-carboxy-B-methylpyridone-2 with ammonia to form the amide ot s-cyano-i-carboxy- B-methylpyridone-2.

2. In the processor preparing vitamin Be, the step which comprisesdehydrating the amide oi 3-cyano-4-carboxy-6-methyl pyridone-2 to form3,4-dicyano-6-methyl pyridone-2.

3. In the process of preparing vitamin Be, the step which comprisesnitration of 3,4-dicyano- 8-methyl pyridone-2.

4. In the process of preparing vitamin Be, the step which compriseshalogenating 3,4-dicyano- S-nitro-G-methyl pyridone-2 with ahalogenating substance 01' the group consisting of chlorimating andbrominating reagents to form 2-ha1ocyano-4-carboxy-6-methyl pyridone-2with ammonia to form the amide of 3-cyano-4-carboxy- G-methylpyridone-2, dehydrating the latter to give 3,4-dicyano-6-methy1pyridone-2, nitrating to form 3,4-dicyano-5-nitro-6-methyl pyridone-il,halogenating the latter. to form 2-halo-3,4-dicyano-5-nitro-6-methylpyridin, reducing the nitro group to give 2-halo-3,4-dicyano-5-amino-G-methyi pyridin, reducing the cyano groups to iorm3,4-aminomethyl-5-amino-6-methyl pyridin and deaminating to form vitaminBe.

13. In the process of preparing vitamin 134, the steps which comprisereacting the ethyl ester of 3-cyano-4-carboxy-6-methyl pyridone- 2 withammonia to form the amide of 3-cyano-4-carboxy-G-methyl pyridone-2,dehydrating the latter to give 3,4-dicyano-6-methyl pyridone-2,nitrating to form 3,4-dicyano-p-nitro-fi-methyi pyridone-2, chlorinatingthe latter to form 2-chiorostep which comprises reduction of a substanceoi the group consisting of 2-chloro-3,4-dicyano- 5-am'ino-6-methy1pyridin and 2-bromo-3,4- dicyano-5-amino-6-methyl pyridin to form a 3,4-aminomethyl-5-amino-6-methyl pyridin.

9. In the process of preparing vitamin Be, the

trating to form 3,4-dicyano-5nitro-G-methyl pyridone-2, brominating thelatter to i'orm 2- bromo-3,4-dicyano-5-nitro-6-methyl pyridin, reducingthe "nitro group to give 2-bromo-3,4- dicyano-5-amino-6-methyl pyridin,reducing the cyano groups to form 3,4-aminomethyl-5-amino- G-methylpyridin trihydrochloride, and deaminating the trihydrochloride to formvitamin B0.

15. The compounds of the group consisting of3,4-aminomethyl5-amino-6-methyl pyridin and acid addition salts thereof.

16. The compound of the formula:

C HINHI NET-I CmNH.

17. The compound 3,4-aminomethyl-5-amino- B-methyl pyridintrihydrochloride.

18. The compound 3,4-aminomethyl-5-amino- B-methyl pyridintrihydrobromide.

. GUSTAF I-I. CARISON.

